Delta9-dehydro-21-haloethisterones and the process for the production thereof



United States Patent 3,096,353 A -DEHYDRO-2l-HALOETHISTERONES AND THE PROCESS FOR THE PRODUCTION THEREOF John Fried, Plaintield, and Thomas S. Bry, Elizabeth, NJ., assignors to Merck & Co., Inc, Rahvvay, N.J., a

corporation of New Jersey No Drawing. Filed Aug. 3, 1961, Ser. No. 128,977

9 Claims. (Cl. 260-397.4)

.norethisterones and their 17-esters; and the 3-eno1 ethers and the 3-enol ether-17-esters of 21-halonorethisterones, their M -isomers and A -dehydro derivatives, subject of the present invention, possess useful therapeutic properties as orally and parenterally active progestational agents.

This application is a continuation-in-part of application Serial No. 99,668, filed March 31, 1961, which, in turn, is a continuation-in-part of application Serial No. 88,575, filed March 2, 1961, now Patent No. 3,072,646.

The 3-enol ethers of 21-halonorethisterone and their A -isomers (i.e., l7a-halocthynyl-l9-nor-3,S-androstadiene-3,17fi-diol 3-ether and 17oc-haloethynyl-l9-nor-3, 5(10)-andnostadiene-3,17,6-di0l 3-ether) may be chemically represented as follows:

3,096,353 Patented July 2, 1963 androstadiene-lfione which has the following structural formula:

This 3-methoxy-19-nor-2,5 l0)-androstadiene 17 -one is reacted with a haloethyne to form the corresponding 17ahaloethynyl-Ii-methoxy l9 nor-2,5(lO )-androstadiene- 1713-01, which has the following structural formula:

ozox wherein X stands for chloro, bromo, or fluoro.

In a preferred embodiment of this procedure, the haloethyne is formed in situ by the reaction of a. 1,2-dihaloethylene (preferably the cis form) and methyl lithium. For example, the l7a-chlonoethynyl-3-methoxy-19-nor- 2,5(10)-androstadiene-l7B-ol is prepared by adding a solution of cis-l,2-dichloroethylene in ether to a solution of methyl lithium at about 0 C. in ether. The reaction mixture is stirred under nitrogen for 1-2 hours, and to the resulting solution containing the chloroethyne is added 3-methoxy-19-nor-2,5( l0) androstadiene-17-one, and stirring is continued dfior several hours longer.

The l7a-haloethynyl-3-methoxy-19-nor-2,5 (10)-androstadiene-l7fi-ol is converted into the l7a-haloethynyl-l7fihydroxy-l9-nor-4-androstene-3one (i.e., the ZI-halonorethisterone) which has the following formula:

diene-3,17;3-dio1 B-ethers, and their 17-esters) which have the following formulae:

wherein X stands for chloro, bromo, or fluoro, R is a hydrocarbon or substituted hydrocarbon substituent as, for example, an aliphatic or substituted aliphatic radical such as alkyl, or aralkyl, more particularly, methyl, ethyl,

"butyl, amyl, benzyl, a cycloaliphatic or cycloalkyl grouping such as cyclopentyl, cyclohexyl, and the like, and R stands for an acyl radical, for example, a lower hydrocarbon carboxylic acyl radical such as benzoyl, a lower alkanoyl radical such as acetyl, propionyl, butyryl, and the like, by stirring together a mixture of the steroid and an alkyl, cycl-oalkyl or aralkyl orthoforrnate in diox-ane solution in the presence of a strong acid catalyst, for example, organic sulfonic acid.

In a preferred procedure, the novel l7a-haloethynyl- 17,3-hydroxy-19-nor-4-androstene-3-one 3-enol ethers and l7u-haloethynyl-l7 3-acyloxy 19-nor-4-androstene 3-one 3-enol ethers are prepared by adding an alkyl orthoformate, a cycloalkyl orthoformate, or aralkyl orthoformate, such as ethyl orthoformate, propyl orthoformate,

.n-butyl orthoformate, cyclopentyl orthoformate, cyclopentyl orthoformate, cyclohexyl orthoformate, benzyl or- .thoformate, and the like, and an acidic catalyst such as 2,4-dinitrobenzene sulfonic acid, p-toluene-sulfonic acid, and the like, to a solution of the steroid in an organic solvent such as dioxane or preferably the alcohol corresponding to the particular alkyl orthoformate, cycloalkyl onthoformate, or aralkyl orthoformate employed, and stirring the resulting mixtures together at room temperature. The acidic cataylst is then neutralized with a base such as pyridine, and the l7a-haloethynyl-17B-hydroxy-19-nor-4- androstene-3-one 3-enol ether or 17a-haloethynyl-17B- acyloxy-l9 nor-4-androstene-3-one 3-enol ether, as for example, 3-alkoxy l7a-haloethynyl l9-n0r-3,5-androstadiene-17/3-ol, such as S-ethoxy-17ot-chloroethynyl-19-nor- 3,5-androstadiene-17fi-ol; 3-propoxy-17u-fluoroethynyl-19 nor-3,5-androstadiene-175-01; 3-n-butoxy-17a-cholr0ethynyl-19-nor-3,5-androstadiene-1713-01; 3 cycloalkoxy-17ahaloethynyl-19-nor-3,5-androstadiene-17,8-01, such as 3- cyclopentyloxy 17u-ch1oroethynyl 19-nor-3,5-androstadiene-17B-ol; 3-benzy1oxy-17a-fluoroethynyl 19-nor-3,5- androstadiene-Ufi-ol; 3-hexyloxy-17a-chloroethynyl-l9- nor-3,5-andrstadiene-17,8-01; 3-aralkoxy-17ot-haloethynyll9-nor-3,5-androstadiene-17 8-ol, such as 3-benzyloxy-17achloroethynyl-l9-nor-3,S-androstadiene-175-01; 3-benzyloxy-17a-fluoroethynyl-19-nor-3,5-androstadiene-l7fl-ol; 3- alkoxy 17a-haloethynyl-17/8-alkanoyloxy 19-nor-3,5-androstadiene, such as 3-ethoxy-l7a-chloroethynyl-l7B-acetoxy-19-nor-3,5-androstadiene; 3-propoxy-17a-fluoroethynyl-17B-acetoxy l9-nor-3,5-androstadiene; 3-n-butoxy- 17a-chloroethyny1- 17;9-propionoxy-l9-nor 3,5-androstadiene; 3-cyc1oalkoxy-17a-haloethynyl-l7p-alkanoyloxy-19- nor-3,5-androstadiene, such as S-cyclopentyloxy-l7a-chloroethynyl-l7fi-acetoxy-l9-nor-3,5--androstadiene; 3-benzyloxy-17wfluoroethynyl-17,6-hutyroxy 19-nor-3,5-androstadiene; 3-hexyloxy-l7ot-chloroethynyl-17/3-acetoxy-19-nor- 3,5-androstadiene; 3-aralkoxy-17ot-haloethynyl-17B-alkanoyloxy-l9-nor-3,5-androstadiene, such as 3-benzlyoxy- 17a-chloroethynyl 17B-propionoxy 19-nor-3,5-androstadiene; 3-benzyloxy-17a-fiuoroethyny1-17fi-acetoxy-l9-nor- 3,5-androstadiene; and the like, are recovered from the neutralized reaction mixture.

The 17a-haloethynyl-l7;8-hyrdoxy'l9-nor-4-androstene- 3-one 3-enol ethers, other than the 3-enol ethyl ethers, are conveniently prepared starting with said 3-enol ethyl ether (e.g., 3-ethoxy-17a-haloethyny1-19-nor-3,5-androstadiene-l7fi-ol) by mixing together the latter compound and an inert hydrocarbon solvent such as isoctane and an alcohol such as, for example, an aliphatic alcohol such as propanol, n-butyl alcohol, amyl alcohol, a cycloaliphatic alcohol, as for example, a cycloalkanol such as cyclohexanol, cyclopentanol, an araliphatic alcohol, as, for example, an aralkanol such as benzyl alcohol, and the like, and an acidic catalyst such as p-toluenesulfonic acid, and heating the resulting mixture, preferably under reflux, in an apparatus equipped with means for removing the Water from the distillate and returning the dry distillate to the reaction mixture. The acid catalyst is then neutralized with a base such as pyridine, and the resulting neutral solution is evaporated to dryness in vacuo to give the 170:-

haloethynyl-17,6-hydroxy-l9-nor-4-androstene 3-enol ether, which is conveniently purified by crystallization from methanol containing traces of pyridine, or by chromotography.

The 6-chloro- 17 a-haloethynyl- 17 fl-hydroxy- 19-nor-4,6- androstadiene-Ii-one may be prepared in a multiple-step process from the 3-enol ethers of the 17ot-haloethynyl-17B- hydroxy-l9-nor-4-androstene-3-one by reaction first with N-bromosuccinimide to give '6fl-bromo-l7a-haloethynyl- 17,8-hydroxy-l9-nor-4-androstene-3-one which has the following formula:

wherein X is chloro, bromo or fiuoro. In a preferred procedure, a solution of the steroid and sodium acetate in aqueous acetone is stirred with N-bromosuccinimide and acetic acid at about 0 C.

The 17fl-lower alkanoyl esters of 17fi-hydroxy-17othaloethynyl-3-keto-steroids, such as l7fi-hydroxy-17achloroethynyl 19-nor-4-androstene-3-one, 17 8-hydroxyl7a-bromoethynyl 19-nor-4-androstene 3-one, 17B-hydroxy-lh-chloroethynyl 19-nor-4,9-androstadiene-3-one, 17fi-hydroxy 17a-bromoethyny1 19-nor 4,9-androstadiene-3-one, are prepared by the reaction of the 17,8-hydroxy-17a-haloethynyl-3-ketosteroid with a lower alkanoic acid anhydride in the presence of an organic base such as pyridine. The lower acid anhydrides which are ordinarily used include acetic anhydride, propionic anhydride, butyric anhydride, and the like.

' The d-bromo-derivative is then dehydrobrominated to introduce a A bond thus forming the 17u-haloethynyl- 17 8-hydroxy-19-nor-4,6-androstadiene-3-one Which has the following formula:

no ozox wherein X is chloro, bromo, or fluoro, conveniently by treating a solution of the steroid in a solvent such as benzone with perbenzoic acid in the dark at room temperature for about 60-70 hours.

A solution of the 6a,7a-epoxy-17a-haloethynyl-17fi-hydroxy-19-nor-4-androstene-3-one in an organic solvent is treated with CHCl at room temperature to form 6-chloro- 17a-haloethynyl 17,8-hydroxy 19-nor-4,6-androstadiene- 3-one which has the following formula:

wherein X is chloro, bromo, or fiuroro.

The 17a-haloethynyl-3-methoxy-19-nor-2,5 l) -androstadiene-l'lfl-ol may be converted into 17a-haloethynyl- 17fi-hydroxy-l9-nor-5(l0)-androstene-3-one which has the following formula:

no pzo-x wherein X stands for chloro, bromo, or fluoro, by reaction with a Weak organic acid such as acetic acid. For example, a mixture of the steroid and glacial acetic acid in an aqueous solution of absolute ethanol and dioxane is left standing at room temperature for several hours.

The 17u-haloethynyl-17r3-hydroxy-19-nor-4,9-androstadiene-3-one which has the following formula:

HO ozo-oc wherein X stands for chloro, bromo or fluoro, may be prepared by treatment of l7a-haloethynyl-17,8-hydroxy- '19-nor-5(10)-androstene-3-one with approximately one equivalent of bromine in pyridine solution, or with pyridine perbromide hydrobromide.

The following examples illustrate methods of carrying 6 out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example I A solution consisting of 1.7 g. (1.32 cc.) of cis-1,2-dichloroethylene in 10 cc. of sodium-dried ether is added over 0.5 hour at 0 C. to 3 cc. of a 1.4 N-solution of methyl lithium (prepared by adding lithium to methyl iodide in dry ether solution under nitrogen at about 10 C.) in 25 cc. of sodium-dried ether. The reaction mixture is stirred at room temperature under nitrogen for an additional 1 /2 hours, followed by the addition, over a 15- minute period, of mg. of 3-rnethoxy-l9-nor-2,5(10)- androstadiene-l7-one in 4 cc. of sodium-dried ether. The mixture is left stirring at room temperature overnight, poured into ice water and extracted with ether. The ether extracts are Washed with water, dried over sodium sulfate and concentrated in vacuo. The residue is chromatographed on 10 g. of basic alumina. The product is eluted with petroleum etherzether 8:2. Crystallization from acid-free methanol aifords 48 mg. of 17a-chloroethynyl-S-methoxy 19-nor-2,5 10 -androstadiene-l7p-ol, M.P. 112-115 C.

LR. my? 2.80, 4.48, 6.02, 6.12;

A solution consisting of 10 mg. of 17a-ch-loroethynyl- 3-methoxy-19-nor-2,5(1 0)-androstadiene-l7B-ol, 2 cc. of acetone and 2 mg. of p-toluenesulfonic acid is left standing at room temperature overnight. The reaction mixture is then poured into ice water and extracted with ether. The ether extract is Washed with aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated in vacuo. Crystallization from ethyl acetate afrords 17a chloroethynyl-l7B-hydroxy 19-nor-4-androstene-3-one, M.P. l90 C.,

LR. A531? 2.95, 4.50, 6.10, 6.21;;

upon further recrystallization, M.P. 198-201" C.

In accordance with the above procedure, but starting with the l7a-bromoethynylor 17a-fiuoroethynyl-3- methoxy-l9-nor-2,5(10)-androstadiene-l7B-ol in place of the 17ot-chloroethynyl-3-rnethoxy-l 9-no-r-2, 5 10 androstadiene-l7B-ol there is obtained as products the corresponding 17a-bromoethynylor 17a-fluoroethynyl-17B hydroxy-1-nor-4-androstene-3-one.

Example 3 To a solution of 100 mg. of 17a-chloroethynyl-17flhydroxy-19-nor-4-androstene-3-one in 3 cc. of dioxane is added 2 cc. of ethyl orthoformate and 10 mg. of ptoluenesulfonic acid. The reaction mixture is stirred at room temperature for 3 hours and 1 cc. of pyridine is added, followed by the dropwise addition of 5 cc.of water.

The aqueous phase is separated and extracted with benzene. The organic extracts are washed with a sodium bicarbonate solution and then with water until the washings are neutral. The organic phase is dried over sodium sulfate and concentrated in vacuo to give 3-6thOXy-17OL chloroethynyl-l9-nor-3,5-androstadiene-17/3-ol.

LR. 7&3? 2.86, 4.50, 6.05, 6.15;:

In accordance with the above procedure, but starting with the 17a-bromoethynylor the 17ot-fiuoroethynyl-17/3- hydroxy-19-nor-4-androstene-3-one in place of the 170L- chloroethynyl 17,8 hydroxy-l9-nor-4-androstene-3-one there are obtained as products the corresponding 17ozbromoethynyl-or the 17ot-fluoro-ethynyl-3-ethoxy-l9-nor 3,5-androstadiene-17fi-ol.

Example 4 A mixture of 100 mg. of l7a-chloroethynyl-17fl-hydroxy-19-nor-4 androstene-3-one, 0.06 g. of 2,4-dinitrobenzenesulfonic acid, 3 ml. of dry dioxane and 0.25 ml. of freshly distilled n-butyl orthoformate are stirred overnight at 30 C. The acid catalyst is then neutralized by addtiion of 0.1 ml. of pyridine. The reaction mixture is diluted with water and extracted with ether. The combined ether extracts are washed with water, dried and evaporated under reduced pressure. The residue is chromatographed over alumina (alkaline) and eluted with mixtures of ether and petroleum ether to separate 3- butoxy-17u-chloroethynyl-l9-nor-3,5-androstadiene 17 ,8- 01.

In accordance with the above procedure, but starting with the 17a-bromoethyny1- or the 17a-fluoroethynyl-17B- hydroxy-19-nor-4-androstene-3-one in place of the 17erchloroethynyl 175 hydroxy-19-nor-4-androstene-3-one there are obtained as products the corresponding 17abromoethynylor the 17e-fluoroethynyl-3-butoxy-19-nor- 3,5 androstadiene-17fi-ol.

Example 5 A solution consisting of 1 g. of 3-ethoxy-17a-chloroethynyl-19-nor-3,5-androstadiene-173-01, 700 mg. of sodium acetate, 5 ml. of water and 40 ml. of acetone is cooled to C. and 1.07 g. of N-bromosuccinimide and 0.83 ml. of acetic acid is added. The mixture is stirred for 3 hours at 0.5 C. and then poured into water to yield the 6(3-bromo-17a-chloroethynyl-17fi-hydroxy-l9- nor-4-androstene-3-one.

Treatment of 6B-bromo-17u-chloroethynyl-17 8-hydroxy-19-nor-4-androstene-3-one (1.0 g.) with 1.0 g. of lithium bromide, 500 mg. of lithium carbonate and 20 ml. of dimethylformamide for 5 hours at 120 C., follower by dilution with ice water and filtration affords 17achloroethynyl 17,8 hydroxy-19-nor-4,6-androstadiene-3- one.

A solution consisting of 675 mg. of 17a-chloroethyny1- 17fi-hydroxy-19-nor-4,6-androstadiene-3 one, 30 ml. of 0.2 N-perbenzoic acid dissolved in benzene and 30 ml. of ether is allowed to stand at room temperature in the dark for 68 hours. The resulting benzene-ether solution is washed with acidified sodium bisulfite solution, water, 2.5 N-potassium hydroxide solution, and again with water. The washed benzene-ether reaction solution is dried and evaporated in vacuo to give 6oz,7ocpOXy17a.- chloroethynyl-17,8-hydroxy-19-nor-4-androstene-3-one.

The 60,70L-6POXY 17a chloroethynyl-17fl-hydroxy-19- nor-4 androstene-3-one is dissolved in 20 ml. of a 0.4 N solution of hydrogen chloride in chloroform, and the resulting solution is allowed to stand for 5.5 hours at room temperature. The reaction solution is then poured into iced sodium bicarbonate solution. The aqueous mixture is extracted with chloroform, and the chloroform extract is evaporated to dryness in vacuo. The residual material is chromatographed on acid-washed alumina (20 g.) and eluted with ether-petroleum ether mixtures to give 6- chloro 17cc chloroethynyl 17 8 hyd-roxy 19 nor-4,6- androstadiene-El-one.

In accordance with the above procedures, but starting with the 3-ethoxy-(17or-bromoethynylor 17oc-flt1010- ethynyl)-19-nor-3,S-androstadiene-Ufl-ol in place of the S-ethoxy-17a-chloroethynyl-19-nor-3,5-androstadiene-17/3- 01 there are obtained as products the corresponding 6-chloro-(17a-bromo-ethynylor 17a-fluoroethynyl)-17flhydroxy-19-nor-4,6-androstadiene-3-one.

Example 6 To a solution of mg. of 17a-chloroethynyl-3-methoxy-l9-nor-2,5(l0)-androstadiene-17p-ol in 1.6 cc. of dioxane and 7.2 cc. of absolute ethanol is added 3.2 cc. of glacial acetic acid, and immediately thereafter, 1.6 cc. of water. This reaction mixture is left standing at room temperature for 5 hours. -It is then poured into an ice/ sodium bicarbonate solution, allowed to stand until the mixture is basic and extracted with benzene. The benzene extracts are washed with water until the washings are only slightly basic and then dried over anhydrous potassium carbonate, filtered and concentrated in vacuo using a water bath at 3050 C. By crystallization of the residual material from ether, about 9 0 mg. of l7a-chloroethynyl- 1718-hydroxy-19-nor-5 l0)-androstene-3-one is obtained. U.V. no m'ax.;

LR. k213i" 2.98, 4.50, 5.9044

In accordance with the above procedures, but starting with the 17a-bromoethynylor the 17a-fluoroethynyl-3- methoxy-19-nor-2,5(10)-androstadiene-17p-ol in place of the 17a-ch1oroethynyl-3-methoxy-19-nor-2,5'( l0) -andros tadiene-IZB-ol there are obtained as products the corresponding l7a-bromoethynylor l7u-chloroethynyl-l7/3- hydroxy-l9-nor-5 10 -androstene-3-one.

Example 7 To 100 mg. of 17a-chloroethynyl-17fl-hydroxy-l9-nor- 5(10)-androstene-3-one in 5 cc. of pyridine is added one equivalent of bromine. The reaction mixture is stirred for two hours at room temperature, poured into ice water and the aqueous mixture extracted with ether. The ether extract is washed with water, dried over sodium sulfate, and concentrated in vacuo to yield 17a-chloroethyny1-l7flhydroxy-19=nor-4,9-androstadiene-3-one.

In accordance with the above procedures, but starting with the 17a-bromoethynylor the c-filt0106thYDY1-17/8- hydroxy-19-nor-5'(10)-androstene-3-one in place of the 17u-chloroethynyl-171i-hydroxy-19-nor-5 l0) -androstene- 3-one there are obtained as products the corresponding 17a-bromoethynylor the 17a-fluoroethynyl-17,8-hydroxy- 19-nor-4,9-androstadiene-3-one.

Example 8 To 100 mg. of 17a-chloroethynyl-17e-hydroxy-19-nor- 5'(10)-androstene-3-one in 5 cc. of pyridine is added one equivalent of bromine. The reaction mixture is stirred for fifteen hours at room temperature, poured into ice water and the aqueous mixture extracted with ether. The ether extract is washed with water, dried over sodium sulfate, and concentrated in vacuo to yield l7a-chloroethynyl-17fi-hydroxy-19-nor-4,9-androstadiene-3-one.

In accordance with the "above procedures, but starting with the 17a-bromoethynylor the 17u-fluoroethynyl-17flhydroxy-19-nor-5(10)-androstene-3-one in place of the 17a-chloroethyny1-l713-hydroxy-19-nor-5 10) androstene- 3-one there are obtained as products the corresponding 17a-brcmoethynylor the l7a-fluor-oethynyl-175-hydroxy- 19-nor-4,9-androstadiene-3-one.

Example 9 A mixture of 50 mg. of 3-ethoxy-l7a-chloroethynyl- 19-nor-3,5-androstadiene-175-01, 5.5 ml. of isooctane, 25 mg. of cyclohexanol and 2.5 mg. of p-toluenesulfonic acid is heated under reflux for a period of approximately 32 hours in an apparatus providing for the separation of water from the condensate before return to the refluxing mixture. The reaction mixture is cooled, 0.1 ml. of pyridine is added to neutralize the p-t-oluenesulfonic acid catalyst, and the liquid is completely evaporated in vacuo to dryness to give as the residual product 3-CYClOl'l6XYlOXY-17occhloroethynyl-l9-nor-3,5-androstadiene-175-01.

In accordance with the above procedure, but starting with 3-ethoxy-17a bromoethynyl l9 nor 3,5 andros- 9 tadiene-l7p-ol in place of the 3 etlroxy 17a chloroethynyl-l9-nor-3,S-androstadiene-175-01, there is obtained as product the corresponding 3-cyclohexyloxy-17a-bromoethynyl-l9 nor-3,5-androstadiene-175-01. Similarly, when 3-ethoxy-17ct-fiuoroethynyl 19 nor 3,5 androstadiene- 17/3-01 is utilized as starting material in the foregoing procedure, there is obtained as product the corresponding 3-cyclohexyloxy-'17ot-fluoroethynyl l9 nor 3,5 androstadiene-l7 6-ol.

Example 10 A mixture of 50 mg. of 3-ethoxy-17u-chloroethynyl- 19-nor-3,5-androstadiene-17p-ol, 5.5 ml. of isooctane, 25 mg. of n-butanol and 2.5 mg. of p-toluenesulfonic acid is heated under reflux for a period of approximately 32 hours in an 'apparatus providing for the separation of water from the condensate before return to the refluxing mixture. The reaction mixture is cooled, 0.1 ml. of pyridine is added to neutralize the p-toluenesulfonic catalyst, and the liquid is completely evaporated to dryness in vacuo to give as the residual product 3-n-butoxy-17a-chloroethynyl- 19-nor-3,5-androstadiene-17fl-ol.

In accordance with the above procedure, but starting with 3-ethoxy 17cc bromoethynyl-l9-nor-3,5-androstadiene-17fi-ol in place of the 3-ethoxy-17wchloroethynyl-19- nor-3,5-androstadiene-17,8-01, there is obtained as product the corresponding 3-n-butoxy-l7a-bromoethynyl-l9-nor- 3,5-androstadiene-175-01. Similarly, when 3-ethoxy-17afluoroethynyl-l9-n0r-3,S-androstadiene-175-01 is utilized as starting material in the foregoing procedure, there is obtained as product the corresponding 3-n-butoxy-17afluoroethynyl-l9-nor-3,5-androstadiene-17 8-01.

Example 11 A mixture of 50 mg. of 3-ethoxy-17a-chloroethynyl-19- nor-3,5-androstadiene-17B-ol, .5 ml. of isooctane, 25 mg. of cyclopentanol and 2.5 mg. of p-toluenesulfonic acid is heated under reflux for a period of approximately 32 hours in an apparatus providing for the separation of water from the condensate before return to the refluxing mixture. The reaction mixture is cooled, 0.1 ml. of pyridine is added to neutralize the p-toluenesulfonic catalyst, and the liquid is completely evaporated in vacuo to dryness to give as the residual product 3-cyclopentyloxy-l7achloroethynyl-l9-nor-3,5-androstadiene-17/3-ol.

In accordance with the above procedure, but starting with 3-ethoxy 170a bromoethynyl-19-nor-3,S-androstadiene-17fl-ol in place of the 3-ethoxy-17a-chloroethynyl-19- nor-3,5-androstadiene-17,8-01, there is obtained as product the corresponding 3-cyclopentyloxy-17a-brornoethynyl- 19-n0r 3,5 androstadiene-17/3-ol. ethoxy-l7a-fluoroethynyl-l9-nor-3,5-andr0stadiene-175-01 is utilized as starting material in the foregoing procedure, there is obtained as product the corresponding 3-cyclopentyloxy 17a fluoroethynyl-19-nor-3,5-androstadiene- 17,8-01.

Example 12 A mixture of 50 mg. of 3-ethoxy-17a-chloroethynyl-19- nor-3,5-androstadiene-175-01, 5.5 ml. of isooctane, 25 mg. of benzyl alcohol and 2.5 mg. of p-toluenmulfom'c acid is heated under reflux for a period of approximately 32 hours in an apparatus providing for the separation of Water from the condensate before return to the refluxing mixture. The reaction mixture is cooled, 0.1 ml. of pyridine is added to neutralize the p-toluenesulfonic catalyst, and the liquid is completely evaporated in vacuo to dryness to give as the residual product 3-benzyloxy- 17ot-chloroethynyl-l9-nor-3,5-androstadiene-175-01.

In accordance with the above procedure, but starting with 3-ethoxy-l7a-bromoethynyl-19-nor-3,5-androstadiene-17fl-ol in place of the 3-ethoxy-l7a-chloroethynyl-19- nor-3,5-androstadiene-175-01, there is obtained as product the corresponding 3-benzyloxy-l7a-bromoethynyl-19-nor- 3,5-androstadiene-175-01. Similarly, when 3-ethoxy-17afluoroethynyl-l9-nor-3,S-androstadiene-175-01 is utilized Similarly, when 3- r as starting material in the foregoing procedure, there is obtained as product the corresponding 3-benzyloxy-l7ufiuoroethynyl-19-nor-3,5-androstadiene-17B-ol.

Example 13 One-hundred mg. of 17ot-chloroethynyl-Uri-hydroxy- 19-nor-4,9-androstadiene-3-one is heated with 1 cc. of acetic anhydride and 1.2 cc. of pyridine on the steam bath overnight. The reaction mixture is then poured onto ice and extracted with chloroform. The extract is washed with Water and concentrated. The concentrate is chromatographed over acid-Washed alumina and eluted with mixtures of ether and petroleum ether to give 17B-acetoxy- 17a-chloroethynyl-19-nor-4,9-androstadiene-3-one.

Example 14 One-hundred mg. of 3-cyclopentyloxy-Not-chloroethynyl-l9-nor-3,5-androstadiene-17fl-o1 is heated with 1 cc. of acetic anhydride and 1.2 cc. of pyridine on the steam bath overnight. The reaction mixture is then poured onto ice and extracted with chloroform. The extract is chromatographed over acid-Washed alumina and eluted with mixtures of ether and petroleum ether to give 3-cyclopentyloxy 17B acetoxy-17a-chloroethylnyl-19-nor 3,5- androstadiene.

Example 15 A mixture of 736 mg. of 17ot-chloroethynyl-19-nor-4- androstene-l7p3-ol-3-one, 2.1 g. of cyclopentyl orthoformate, 7.4 ml. of cyclopentanol and 30 mg. of p-toluenesulfonic acid is stirred under an atmosphere of nitrogen for a period of 3.5 hours. The reaction mixture poured into ice-cold aqueous sodium bicarbonate solution, and the aqueous mixture extracted with ethyl ether. The ethyl ether extract is separated, dried, and evaporated to dryness in high vacuum at a temperature not exceeding 50 C. to give 3-cyclopentyloxy-17a-chloroethynyl-19- nor-3,5-androstadiene-l7(3-01 which is purified by chromatography on silicia gel.

In accordance with the above procedure, but starting with 17a-bromoethynyl-19-nor-4-androstene-17 8-ol-3-one in place of the 17a-chloroethynyl-19-nor-4-androstene- 17B-ol-3-one, there is obtained as product the corresponding 3-cyclopentyloxy 17a brorn'oethynyl-19-nor-3,5-androstadiene-17p-ol. And similarly, when 17a-fluoroethynyl-l9-nor-4-androstene-l7fl-ol-3-one is utilized as starting material in the foregoing procedure, there is obtained as product the corresponding 3-cyclopentyloxy-l7afluoroethynyl-19-nor-3,S-androstadiene-1713-01.

Example 16 A mixture of 736 mg. of 17ot-chloroethynyl-19-nor-4,9- androstadiene-17B-ol-3-one, 2.1 g. of cyclopentyl orthoformate, 7.4 ml. of cyclopentanol and 30 mg. of p-toluenesulfonic acid is stirred under an atmosphere of nitrogen for a period of 3.5 hours. The reaction mixture is poured into ice-cold aqueous sodium bicarbonate solution, and the aqueous mixture extracted with ethyl ether. The ethyl ether extract is separated, dried, and evaporated to dryness in high vacuum at a temperature not exceeding 50 C. to give 17ot-chloroethynyl-l9-nor-4,9-androstadiene-17,8-ol-3-one-3-cyclopentyl enol ether which is puri fied by chromatography on silica gel.

Various changes and modifications may be made in carrying out the present invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. a haloethynyl 17,8 hydroxy 19-nor-4,9'(10)- androstadiene-3-one.

2. 17a haloethynyl 17B acyloxy l9 nor-4,9( 10)- androstadiene-3cne.

3. 170: haloethynyl hydroxy 19 nor-49(10)- androstadiene-3-one 3-enol ether.

1 1 12 4. 170a haloethynyl 175 acyloxy 19 nor-4,9 (10)- 8. 1700 chloroethynyl 17B acetoxy-19-nor-4,9(10)- androstadiene-B-one 3-eno1 ether. androstadiene-3-one 3-cyc1openty1 enol ether.

5. 17oz chloroethynyl 17E hydroxy 19-11or-4,9(10)- 9. The process for the preparation of 17ot-ha1oethyny1- d t dj -3. 17,8 hydroxy 19 nor 4,9(10) androstadiene-S-one 6- 1706 chloroethynyl 17,3 acetOXy 19 nor 4,9(1O) 5 which comprises reacting 17x-haloethyny1-17 8-hydroXyandrostadieneswne 19-nor-5(10)-androstene-3-one with approximately one 17 chloroethynyl 17B hydmXy 19 nOr 4,9(10) equivalent Weight of bromine in pyridine solution. androstadiene-3-one 3-cyclopentyl enol ether. No references cited. 

1. 17A-HALOETHYNYL - 17B- HYDROXY - 19-NOR-4,9(10)ANDROSTADIENE-3-ONE. 